Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations

Abstract

STUDY QUESTION Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility? SUMMARY ANSWER PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility. WHAT IS KNOWN ALREADY PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD. STUDY DESIGN, SIZE, DURATION In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS Five women aged 19–38 years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients. MAIN RESULTS AND THE ROLE OF CHANCE All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies. LIMITATIONS, REASONS FOR CAUTION The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD. WIDER IMPLICATIONS OF THE FINDINGS The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was used for this study. There are no potential conflicts of interest. TRIAL REGISTRATION NUMBER N/A

Disorders of Sex Development: Classification, Review, and Impact on Fertility

“…It is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1, and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis [148]. In a study by Yatsuga et al [147] on the clinical characteristics of PORD in Japan, it is shown that in many cases, PORD can be diagnosed at <3 months of age.…”

Successful Live Birth in a Chinese Woman with P450 Oxidoreductase Deficiency through Frozen-thawed Embryo Transfer

“…Several phenotypic features were very common in PORD women but occurred across a range of mutations, including of high serum concentrations of P (100%), pregnenolone (100%), 17OHP (96%), corticosterone (83%) and deoxycorticosterone (DOC)(70%), DSD(78%), ovarian cysts(39%), skeletal malformations(84%), and adrenal insu ciency(78%) with most of mild cases [6]. For lateonset PORD primary amenorrhea/oligomenorrhea or infertility could be the main clinical manifestation [7,8,9], but little is known about the optimal way to investigate and treat patients with adult-onset PORD. Our case presented with features of high P and 17OHP, primary amenorrhea, ovarian cyst, minor skeletal malformation and no obvious sign of adrenal insu ciency.…”

“…In a recent published paper from France, PORD was biologically and genetically con rmed in ve adult women with chronically elevated serum P who were referred for oligo-/amenorrhea and/or infertility, and two of these ve PORD women were reported to obtain successful live births by assisted reproductive treatment [9]. However comparing with our case, the two patients had milder clinical phenotypes with oligomenorrhea and infertility, and two different compound heterozygous mutations of c.1249-1G > C/ c.1324C > T and c.1825C > T/ c.1859G > C in POR gene [9]. Our case provided additional information of effective infertility treatment in PORD women with different ethnicity, clinical phenotype and POR gene mutation.…”

“…Patients with PORD occur mostly in neonates and children, and have a range of skeletal malformations, glucocorticoid de ciency and disorders of sexual development (DSD) [6]. Although one pair of POR mutations can impair all microsomal cytochrome P450 enzymes, each enzyme is affected to a different extent (depending on the locations of the POR gene mutations), resulting in high clinical variability of PORD, such as it has been reported that young girls or women only had incomplete pubertal development, primary amenorrhea, oligomenorrhea or infertility with or without skeletal malformations [7,8,9]. The clinical course of PORD in adulthood and the long-term consequence for female fertility remain unknown.…”

Successful live birth in a Chinese woman with P450 oxidoreductase deficiency through frozen-thawed embryo transfer and review of the literature

“…Patients with PORD occur mostly in neonates and children, and have a range of skeletal malformations, glucocorticoid de ciency and disorders of sexual development (DSD) [7]. Although one pair of POR mutations can impair all microsomal cytochrome P450 enzymes, each enzyme is affected to a different extent (depending on the locations of the POR gene mutations), resulting in high clinical variability of PORD, such as it has been reported that young girls or women only had incomplete pubertal development, primary amenorrhea, oligomenorrhea or infertility with or without skeletal malformations [2,22,24]. The clinical course of PORD in adulthood and the long-term consequence for female fertility remain unknown.…”